Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model

Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (\u3b1-GalA) enzyme. \u3b1-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3) in the endothelium and vascular smooth muscles. A hallmark symptom of Fabry disease patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. The \u3b1-GalA gene null mouse model (\u3b1-GalA(-/0)) has provided molecular evidence for the molecular alterations in small type-C nociceptors in Fabry disease that may underlie their hyperexcitability, although the specific mechanism remains elusive. Here, we have addressed this question and report that small type-C nociceptors from \u3b1-GalA(-/0) mice exhibit a significant increase in the expression and function of the TRPV1 channel, a thermoTRP channel implicated in painful heat sensation. Notably, male \u3b1-GalA(-/0) mice displayed a 482-fold higher heat sensitivity than wild-type animals, consistent with the augmented expression levels and activity of TRPV1 in \u3b1-GalA(-/0) nociceptors. Intriguingly, blockade of neuronal exocytosis with peptide DD04107, a process that inhibits among others the algesic membrane recruitment of TRPV1 channels in peptidergic nociceptors, virtually eliminated the enhanced heat nociception of \u3b1-GalA(-/0) mice. Together, these findings suggest that the augmented expression of TRPV1 in \u3b1-GalA(-/0) nociceptors may underly at least in part their increased heat sensitivity, and imply that blockade of peripheral neuronal exocytosis may be a valuable pharmacological strategy to reduce pain in Fabry disease patients, increasing their quality of life